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Abstract:

The present invention relates to substituted sulfonamide compounds of the
general formula (I), wherein P is sulfonamide or amide-substituted
sulfonic acid, which compounds are potentially useful for the prophylaxis
and treatment of medical conditions relating to obesity, type II diabetes
and/or disorders of the central nervous system.
##STR00001##

Claims:

1. A compound of the formula I ##STR00353## or a pharmaceutically
acceptable salt thereof, wherein:ring B is ##STR00354## in which D is a
five-membered heterocyclic or heteroaryl ring, said ring comprising one
or two atoms selected from the group consisting of nitrogen, sulfur and
oxygen, with the proviso that when D contains an oxygen atom, D is
heteroaryl;W is N or --(CH)--, provided that not more than three groups W
are N in both rings A and B together;P is ##STR00355## P and R3 are
bound to the same ring and are disposed in meta- or para-positions
relative to each other;R1 is(a) C1-6 alkyl,(b) C1-6
alkoxyalkyl,(c) straight or branched C1-6 hydroxyalkyl,(d) straight
or branched C1-6 alkylhalides; or(e) a group Ar;Ar is(a) phenyl,(b)
1-naphthyl,(c) 2-naphthyl,(d) benzyl,(e) cinnamoyl,(f) a 5 to 7-membered,
optionally aromatic, partially saturated or completely saturated,
heterocyclic ring containing 1 to 4 heteroatoms, selected from oxygen,
nitrogen and sulfur, or(g) a bicyclic ring system comprising at least one
heterocyclic ring according to (f).wherein the group Ar is substituted in
one or more positions with(a) H, X or Y, or(b) a 5 to 7-membered,
optionally aromatic, partially saturated or completely saturated,
heterocyclic ring each containing 1 to 4 heteroatoms selected from
oxygen, nitrogen or sulfur;R2 is(a) H,(b) C1-6 alkyl,(c)
C1-6 alkoxy,(d) straight or branched C1-6 hydroxyalkyl, or(e)
straight or branched C1-6 alkylhalides;or R1 and R2 are
linked to form a group (CH2)4O;One of R3 is a group
##STR00356## X and Y are independently(a) H,(b) halogen,(c) C1-6
alkyl,(d) --CF3,(e) hydroxy,(f) C1-6 alkoxy,(g) C1-4
alkenyl;(h) phenyl;(i) phenoxy,(j) benzyloxy,(k) benzoyl,(l)
--OCF3,(m) --CN,(n) straight or branched C1-6 hydroxyalkyl,(o)
straight or branched C1-6 alkylhalides,(p) --NH2,(q)
--NHR4,(r) --NR4R5,(s) --NO2,(t)
--CONR4R5,(u) --NHSO2R4,(v) --NR4COR5,(x)
--SO2NR4R5,(z) --C(═O)R4,(aa) --CO2R4,
or(ab) --S(O)nR4; wherein n is 0, 1, 2 or 3;(ac)
--S--(C1-6)alkyl(ad) --SCF3 R4 and R5 are
independently(a) H,(b) C1-6 alkyl,(c) C3-7 cycloalkyl, or(d)
Ar, as defined above for R1;alternatively, R4 and R5 are
linked to form a group (CH2)2O, (CH2)4O or
(CH2)3-5; andR6 is(a) H, or(b) straight of branched
C1-6 alkyl.

2. The compound according to claim 1 of the general formula II
##STR00357## wherein R3, P, X and Y are as defined for formula (I).

3. The compound according to claim 1 of the general formula III
##STR00358## wherein R3, P, X and Y are as defined for formula (I).

4. The compound according to claim 1 of the general formula IV
##STR00359## wherein R3, P, X and Y are as defined for formula (I).

5. The compound according to claim 1 of the general formula V ##STR00360##
wherein R3, P, X and Y are as defined for formula (I).

6. The compound according to claim 1 of the general formula VI
##STR00361## wherein R3, P, X and Y are as defined for formula (I);
and wherein D is a five-membered heterocyclic or heteroaryl ring, said
ring comprising one or two atoms selected from the group consisting of
nitrogen, sulfur and oxygen, with the proviso that when D contains an
oxygen atom, D is heteroaryl. When the heteroaryl ring comprises one or
two nitrogen atoms, a group R6 is attached at the secondary
nitrogen, in which R6 is as defined for formula (I).

13. A process for the preparation of a compound according to claim 1,
wherein P is ##STR00363## said method comprising the steps of:(a)
nucleophilic aromatic substitution of the aromatic halogen atom in
1-chloro-3-nitronaphthalene or 1-chloro-4-nitronaphthalene with aliphatic
or aromatic diamines;(b) reduction of the nitro group in
1-diamine-3-nitronaphthalene or 1-diamine-4-nitronaphthalene obtained in
step (a) to form 1-diamine-3-NH2-naphthalene or
1-diamine-4-NH2-naphthalene, respectively; and(c) synthesis of a
sulfonamide by reacting 1-diamine-3-NH2-naphthalene or
1-diamine-4-NH2-naphthalene obtained in step (b) with a suitable
sulfonyl chloride.

15. A process for the preparation of a compound according to claim 1,
wherein P is ##STR00364## said method comprising the steps of:(a)
nucleophilic aromatic substitution of the trifluoromethanesulfonate group
in 2-trifluoromethansulfonate-5-nitroquinoline with aliphatic or aromatic
diamines;(b) reduction of the nitro group in 2-diamine-5-nitroquinoline
obtained in step (a) to form 2-diamine-5-NH2-quinoline; and(c)
synthesis of a sulfonamide by reacting 2-diamine-5-NH2-quinoline
obtained in step (b) with a suitable sulfonyl chloride.

16. A process for the preparation of a compound according to claim 1,
wherein P is ##STR00365## said method comprising the steps of:(a)
reacting a fluoronaphthalene and chlorosulfonic acid under acidic
conditions, to introduce a sulfonyl chloride group in the para position
to the carbon having the fluoro atom;(b) reacting the product of step (a)
with an aliphatic or aromatic primary amine to give a sulphonamide;
and(c) reaction of the product of step (b) with a diamine.

17. A pharmaceutical formulation containing a compound according to claim
1 as active ingredient, in combination with a pharmaceutically acceptable
diluent or carrier.

18. A method for the treatment or prophylaxis of obesity, type II
diabetes, and/or disorders of the central nervous system, which comprises
administering to a mammalin need of such treatment an effective amount of
a compound according to claim 1.

19. A method for reducing body-weight or reducing food intake, comprising
administering to a subject in need thereof an effective amount of a
compound according to claim 1.

20. A method for modulating 5-HT6 receptor activity, comprising
administering to a subject in need thereof an effective amount of a
compound according to claim 1.

Description:

RELATED APPLICATIONS

[0001]This application is a continuation of U.S. application Ser. No.
11/509,989, filed Aug. 25, 2006, which is pending, which is a divisional
of U.S. application Ser. No. 10/167,141, filed Jun. 11, 2002, now U.S.
Pat. No. 7,144,883, which issued on Dec. 5, 2006, and which claims the
benefit of Swedish application number 0102048-6, filed on Jun. 11, 2001,
Swedish application number 0102386-0, filed on Jul. 3, 2001, and Swedish
application number 0103437-0, filed on Oct. 16, 2001. Each of the
aforementioned applications is incorporated herein by reference in its
entirety.

TECHNICAL FIELD

[0002]The present invention relates to substituted sulfonamide compounds,
to pharmaceutical compositions comprising these compounds, and to the use
of the compounds for the prophylaxis and treatment of medical conditions
relating to obesity, type II diabetes, and CNS disorders.

BACKGROUND ART

[0003]Obesity is a condition characterized by an increase in body fat
content resulting in excess body weight above accepted norms. Obesity is
the most important nutritional disorder in the western world and
represents a major health problem in all industrialized countries. This
disorder leads to increased mortality due to increased incidences of
diseases such as cardiovascular disease, digestive disease, respiratory
disease, cancer and type II diabetes. Searching for compounds, which
reduce body weight has been going on for many decades. One line of
research has been activation of serotoninergic systems, either by direct
activation of serotonin receptor subtypes or by inhibiting serotonin
reuptake. The exact receptor subtype profile required is however not
known.

WO 99/42465 discloses sulphonamides derivatives that bind to the
5-HT6 receptor and that can be used for the treatment of CNS
disorders such as anxiety, depression, epilexy, obsessive compulsive
disorders, cognitive disorders, ADHD, anorexia and bulimia schizophrenia,
drug abuse.WO 01/32646 A1 discloses compounds that binds to the
5-HT6 receptor and that are used for the treatment of CNS disorders
and which inter alia may be used for the treatment of eating disorders.WO
99/37623 A2 discloses compounds that binds to the 5-HT6 receptor and
that are used for the treatment of CNS disorders and which inter alia may
be used for the treatment of eating disorders.WO 99/42465 A3 discloses
compounds that binds to the 5-HT6 receptor and that are used for the
treatment of CNS disorders and which inter alia may be used for the
treatment of eating disorders.EP 0 815 861 A1 discloses compounds that
binds to the 5-HT6 receptor and that are used for the treatment of
CNS disorders.WO 99/02502 A2 discloses compounds that binds to the
5-HT6 receptor and that are used for the treatment of CNS disorders
and which inter alia may be used for the treatment of eating disorders.WO
98/27081 A1 discloses compounds that binds to the 5-HT6 receptor and
that are used for to the treatment of CNS disorders and which inter alia
may be used for the treatment of eating disorders.

DISCLOSURE OF THE INVENTION

[0007]It has surprisingly been found that the compounds of formula (I)
show affinity for the 5-HT6 receptor as antagonists at low nanomolar
range. Compounds according to the invention and their pharmaceutically
acceptable salts have 5-HT6 receptor antagonist activity and are
believed to be of potential use in the treatment or prophylaxis of
obesity and type II diabetes, as well as in the treatment or prophylaxis
of disorders of the central nervous system such as anxiety, depression,
panic attacks, memory disorders, sleep disorders, migraine, anorexia,
bulimia, binge disorders, obsessive compulsive disorders, psychoses,
Alzheimer's disease, Parkinson's disease, Huntington's chorea and/or
schizophrenia, Attention Deficit Hyperactive Disorders (ADHD), drug
abuse.

DEFINITIONS

[0008]Unless otherwise stated or indicated, the term "C1-6 alkyl"
denotes a straight or branched alkyl group having from 1 to 6 carbon
atoms. Examples of said lower alkyl include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and
branched-chain pentyl and hexyl.

[0009]Unless otherwise stated or indicated, the term "C1-6 alkoxy"
denotes a straight or branched alkoxy group having from 1 to 6 carbon
atoms. Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and
branched-chain pentoxy and hexoxy.

[0011]The term "C3-7 cycloalkyl" denotes a cyclic alkyl group having
a ring size from C3 to C7. Examples of said cycloalkyl include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and
cycloheptyl.

[0012]The term "heterocyclic" refers to a hydrocarbon ring system
containing 4 to 8 ring members that have at least one heteroatom (e.g.,
S, N, or O) as part of the ring. It includes saturated, unsaturated,
aromatic, and nonaromatic heterocycles. Suitable heterocyclic groups
include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl,
piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl,
pyrimidinyl, and piperazinyl groups

[0013]The term "heteroaryl" refers to a hydrocarbon ring system having at
least one aromatic ring which contains at least one heteroatom such as O,
N, or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl,
oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl,
and indolyl groups.

Compounds of Formula I

[0014]In a first aspect, the present invention provides a compound having
the general formula I:

##STR00002##

or a pharmaceutically acceptable salt thereof, wherein:W is N or --(CH)--,
provided that not more than three groups W are N;

P is

##STR00003##

[0015]with the proviso that P and R3 can only be in meta or para
position to each other;

[0017](a) phenyl,(b) 1-naphthyl,(c) 2-naphthyl,(d) benzyl,(e)
cinnamoyl,(f) a 5 to 7-membered, optionally aromatic, partially saturated
or completely saturated, heterocyclic ring containing 1 to 4 heteroatoms,
selected from oxygen, nitrogen and sulfur, or(g) a bicyclic ring system
comprising at least one heterocyclic ring according to (f).
[0018]wherein the group Ar is substituted in one or more positions with
[0019](a) H, X or Y, or [0020](b) a 5 to 7-membered, optionally aromatic,
partially saturated or completely saturated, mono- or bi-cyclic
heterocyclic ring each containing 1 to 4 heteroatoms selected from
oxygen, nitrogen or sulfur;

[0027](b) C1-6 alkyl,(c) C3-7 cycloalkyl, or(d) Ar, as defined
above for R1;alternatively, R4 and R5 are linked to form a
group (CH2)2O, (CH2)4O or (CH2)3-5; and

R6 is

(a) H, or

[0028](b) C1-6 alkyl.

[0029]In one aspect, this invention features a compound of the formula
(I):

##STR00005##

or a pharmaceutically acceptable salt thereof, wherein:ring B is

##STR00006##

in which D is a five-membered heterocyclic or heteroaryl ring, said ring
comprising one or two atoms selected from the group consisting of
nitrogen, sulfur and oxygen, with the proviso that when D contains an
oxygen atom, D is heteroaryl;W is N or --(CH)--, provided that not more
than three groups W are N in both rings A and B together;

P is

##STR00007##

[0030]P and R3 are bound to the same ring and are disposed in the
meta- or para-positions relative to each other;

[0032](a) phenyl,(b) 1-naphthyl,(c) 2-naphthyl,(d) benzyl,(e)
cinnamoyl,(f) a 5 to 7-membered, optionally aromatic, partially saturated
or completely saturated, heterocyclic ring containing 1 to 4 heteroatoms,
selected from oxygen, nitrogen and sulfur, or(g) a bicyclic ring system
comprising at least one heterocyclic ring according to (f).
[0033]wherein the group Ar is substituted in one or more positions with
[0034](a) H, X or Y, or [0035](b) a 5 to 7-membered, optionally aromatic,
partially saturated or completely saturated, heterocyclic ring each
containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

R2 is

(a) H,

[0036](b) C1-6 alkyl,(c) C1-6 alkoxy,(d) straight or branched
C1-6 hydroxyalkyl, or(e) straight or branched C1-6
alkylhalides;or R1 and R2 are linked to form a group
(CH2)4O, which represents
(CH2)--(CH2)--O--(CH2)--(CH2);One of R3 is a
group

[0042](b) C1-6 alkyl,(c) C3-7 cycloalkyl, or(d) Ar, as defined
above for R1;alternatively, R4 and R5 are linked to form a
group (CH2)2O, (CH2)4O or (CH2)3-5; in
which (CH2)2O represents (CH2)--O--(CH2) and
(CH2)4O represents
(CH2)--(CH2)--O--(CH2)--(CH2); and

R6 is

(a) H, or

[0043](b) straight of branched C1-6 alkyl.

[0044]In preferred forms, the invention provides naphthalene compounds of
the formula (II), isoquinoline compounds of the formula (III), quinoline
compounds of the formula (IV), 1,7-naphthyridine compounds of the formula
(V), and benzofuran, benzothiophene, or indole compounds of the formula
(VI):

##STR00009##

wherein R3, P, X and Y are as defined for formula (I); and wherein D
in formula (VI) is a five-membered heterocyclic or heteroaryl ring, said
ring comprising one or two atoms selected from the group consisting of
nitrogen, sulfur and oxygen, with the proviso that when D contains an
oxygen atom, D is heteroaryl. The group Y can be attached to any
unsubstituted carbon atom in D. When the heteroaryl ring comprises one or
two nitrogen atoms, a group R6 could be attached at the secondary
nitrogen.Preferred compounds of the general formulas (I), (II), (III),
and (IV), (V), (VI) are those wherein:

R1 is

[0045](a) C1-6 alkyl, or(e) a group Ar;

Ar is

[0046](a) phenyl,(b) 1-naphthyl,(c) 2-naphthyl, or(f) a 5 to 7-membered,
partially or completely saturated, mono- or bi-cyclic heterocyclic ring
each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;wherein the group Ar is substituted in one or more positions with
X or Y; wherein X or Y is

[0050](b) C1-3 alkyl, in particular methyl;or R1 and R2 are
linked to form a group (CH2)4O;

R3 is

##STR00010##

[0052]wherein R6 is

[0053](a) H, or

[0054](b) C1-6 alkyl, in particular methyl;

X and Y are H; and/orD is furanyl.

[0055]Preferred compounds of the formula II are para-substituted
naphthalene compounds wherein P is

##STR00011##

wherein R1 and R2 are as defined for formula (I); and X and Y
are H, halogens, methyl, methoxy, (cf. Table I). Particularly preferred
of such compounds are those wherein R1 is phenyl, methylphenyl,
methoxyphenyl, dimethoxyphenyl, 1-naphthyl, 2-naphthyl,
fluoromethylphenyl, chlorophenyl, dichlorophenyl, fluorochlorophenyl,
dichlorothienyl, chlorothienyl, trifluoromethylphenyl, or
methoxymethylphenyl; R2 is H or methyl; and R3 is piperazinyl
or homopiperazinyl, 3,5-dimethylpiperazine, 4-piperidine,
4-(4,3)-dihydropyridine, 4-(1,2,3,6)-tetrahydropyridine; R6 is H,
methyl, ethyl, isopropyl. Further preferred compounds of the formula II
are compounds with a group P and a group R3 in para-position.

[0056]Further preferred compounds of the formula II are compounds with a
group P and a group R3 in para-position, wherein P is

[0057]Preferred compounds of the formula III are isoquinoline compounds
wherein P is

##STR00013##

and occupies position 3 of the ring, wherein R1 and R2 are as
defined for formula (I); and X or Y are H, methyl, bromo, methoxy,
acetylamino (cf. Table IV). Particularly preferred of such compounds are
those wherein R1 is phenyl, bromophenyl, methylchlorophenyl,
methylphenyl, methoxyphenyl, trimethylphenyl, dimethoxyphenyl,
bromomethoxyphenyl; R2 is H or methyl; and R3 is
methylpiperazinyl.

[0058]Preferred compounds of the formula IV are quinoline compounds
wherein P is

##STR00014##

and occupies position 5 of the ring, wherein R1 and R2 are as
defined for formula (I); and X, Y is H (cf. Table V). Particularly
preferred of such compounds are those wherein R1 is phenyl; R2
is H or methyl; and R3 is piperidinyl.

[0059]Preferred compounds of the formula V are 1,7-naphthyridine compounds
wherein P is

##STR00015##

and occupies position 8 of the ring, wherein R1 and R2 are as
defined for formula to (I); and X and Y are halogen, methoxy (cf. Table
V). Particularly preferred of such compounds are those wherein R1 is
phenyl, dimethoxyphenyl, 1-naphthyl; R2 is H or methyl; and R3
is piperidinyl;

[0060]Preferred compounds of the formula VI are benzofuran compounds
wherein P is

##STR00016##

and occupies position 5 of the ring, wherein R1 and R2 are as
defined for formula (I) and wherein D in formula (VI) is a five-membered
heterocyclic or heteroaryl ring, said ring comprising one or two atoms
selected from the group consisting of nitrogen, sulfur and oxygen, with
the proviso that when D contains an oxygen atom, D is heteroaryl. The
group Y can be attached to any unsubstituted carbon atom in D. When the
heteroaryl ring comprises one or two nitrogen atoms, a group R6
could be attached at the secondary nitrogen; and X and Y are halogen,
methoxy (cf. Table V). Particularly preferred of such compounds are those
wherein R1 is phenyl, dichlorophenyl, bromophenyl,
dichloromethylphenyl, 1-naphthyl, phenyl, methylphenyl, fluorophenyl,
thiophenyl, chlorothiophenyl; R2 is H or methyl; and R3 is
piperidinyl or N-methylpiperidinyl.

[0061]The compounds according to the invention (Tables I, II, IV, V, VI)
can be prepared starting from halo-nitro substituted bicyclic aromatic
rings by base (potassium carbonate) catalyzed aromatic nucleophilic
substitution of a halogen in the desired position of the central bicyclic
ring with the diamine of choice (R3). Reduction of a nitro group
properly positioned on the central bicyclic ring by Raney-Ni catalyzed
reaction leads to the aniline that is to substituted further by
sulfonylation with the alkyl- or aryl-sulfonylchloride of choice
(R1--SO2--Cl). Scheme 1 and Scheme 3

[0062]The compounds according to the invention (Tables III) can be
prepared starting from fluoro substituted bicyclic aromatic rings in
which the sulfonylchloride functionality is is introduced by acid
catalyzed sulfonylation. The sulfonyl group is reacted further with
anilines of choice (R1--NH2). The diamine group (R3) is
introduced by base catalyzed aromatic nucleophilic substitution. Scheme 2

[0063]The compounds according to the invention (Tables VII) can be
prepared starting from iodo substituted bicyclic aromatic rings. The
diamine group (R3) is introduced by Palladium catalysed nucleophilic
substitution. Reduction of a nitro group properly positioned on the
central bicyclic ring by Raney-Ni catalyzed reaction leads to the aniline
that is substituted further by sulfonylation with the alkyl- or
aryl-sulfonylchloride of choice (R1--SO2--Cl). Scheme 4

[0064]The chemicals used in the above-described synthetic route may
include, for example, solvents, reagents, catalysts, protecting group and
deprotecting group reagents. The methods described above may also
additionally include steps, either before or after the steps described
specifically herein, to add or remove suitable protecting groups in order
to ultimately allow synthesis of the compounds of formula (I). In
addition, various synthetic steps may be performed in an alternate
sequence or order to give the desired compounds. Synthetic chemistry
transformations and protecting group methodologies (protection and
deprotection) useful in synthesizing applicable compounds are known in
the art and include, for example, those described in R. Larock,
Comprehensive Organic Transformations, VCH Publishers (1989); T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
2nd Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser
and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994);
and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis,
John Wiley and Sons (1995) and subsequent editions thereof.

[0065]Depending on the process conditions, the end products of the formula
(I) are obtained either in neutral or salt form. Both the free base and
the salts of these end products are within the scope of the invention.

[0066]Acid addition salts of the new compounds may in a manner known per
se be transformed into the free base using basic agents such as alkali or
by ion exchange. The free base obtained may also form salts with organic
or inorganic acids.

[0068]Throughout the specification and the appended claims, a given
chemical formula or name shall encompass all stereo and optical isomers
and racemates thereof where such isomers exist. All diastereomeric forms
possible (pure enantiomers, tautomers, racemic to mixtures and unequal
mixtures of two enantiomers) are within the scope of the invention. Such
compounds can also occur as cis- or trans-, E- or Z-double bond isomer
forms. All isomeric forms are contemplated.

[0069]Pharmaceutical formulations are usually prepared by mixing the
active substance, or a pharmaceutically acceptable salt thereof, with
conventional pharmaceutical excipients. The formulations can be further
prepared by known methods such as granulation, compression,
microencapsulation, spray coating, etc.

[0070]This invention relates to a method of treatment or prophylaxis of
obesity, type II diabetes, and/or disorders of the central nervous
system. The method includes administering to a subject (e.g., a mammal, a
human, a horse, a dog, or a cat) in need thereof an effective amount of
one or more compounds of the formula (I) described above.

[0071]This invention also features a method for reducing body-weight
(e.g., treating body-weight disorders) or reducing food intake. The
method includes administering to a subject in need thereof an effective
amount of a compound of the formula (I). As used herein, the term "body
weight disorders" refers to the disorders caused by an imbalance between
energy intake and energy expenditure, resulting in abnormal body (e.g.,
excessive) weights. Such body weight disorders include obesity.

[0072]Also within the scope of this invention is a method for modulating
(e.g., inhibiting) 5-HT6 receptor activity. The method includes
administering to a subject in need thereof an effective amount of a
compound of the formula (I).

[0073]The methods delineated herein can also include the step of
identifying that the subject is in need of treatment of obesity, type II
diabetes, or disorders of the central nervous system, or in need of
reducing body-weight or reducing food intake.

[0074]"An effective amount" refers to an amount of a compound which
confers a to therapeutic effect on the treated subject. The therapeutic
effect may be objective (i.e., measurable by some test or marker) or
subjective (i.e., subject gives an indication of or feels an effect). For
clinical use, the compounds of the invention are formulated into
pharmaceutical formulations for oral, rectal, parenteral or other mode of
administration. Usually the amount of active compounds is between 0.1-95%
by weight of the preparation, is preferably between 0.2-20% by weight in
preparations for parenteral use and preferably between 1 and 50% by
weight in preparations for oral administration.

[0075]The typical daily dose of the active substance varies within a wide
range and will depend on various factors such as, for example, the
individual requirement of each patient and the route of administration.
In general, oral and parenteral dosages will be in the range of 5 to 1000
mg per day of active substance, preferably 50 to 150 mg per day.

[0076]The specific examples below are to be construed as merely
illustrative, and not limitative of the remainder of the disclosure in
any way whatsoever. Without further elaboration, it is believed that one
skilled in the art can, based on the description herein, utilize the
present invention to its fullest extent. All publications cited herein
are hereby incorporated by reference in their entirety.

[0078]To a solution of nitronapthalenes derivatives (1 eq) in EtOH:THF
(4:1) was added is Raney-Ni (˜1.0 mL suspension in EtOH) followed
by hydrazine monohydrate (6 eq). The mixtures are stirred vigorously for
3 hours and then filtered through celite pretreated with water. The
filtrate was concentrated, followed by the addition of toluene.
Purifications are performed by flash column chromatography (SiO2,
CHCl3/MeOH/NH3 9:1:0.4% and 2 parts of light petroleum) to
obtain the free base of napthylamine derivatives.

General Method B

[0079]Reaction of 4-nitro-chloronaphthalenes with diamines

[0080]Diamines (1.2 eq) are added to a suspension of chloronaphthalenes
derivatives (1 eq) and K2CO3 (3.5) in DMF. The suspensions are
stirred at 65° C. for 16 hours followed by filtration. Elimination
of volatiles to give a crude residue. The residues are purified by flash
chromatography (SiO2, CHCl3→CHCl3/10% MeOH/0.4% aq.
NH3) to give the corresponding products as free bases.

[0081](a) Intermediates for Preparation of Compounds in Tables I, II, IV
and V According to Scheme 1

[0095]tert-Butyl(2R,6S)-2,6-dimethyl-4-(4-nitro-1-naphthyl)-1-piperazineca-
rboxylate--To a solution of
cis-3,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine (0.565 g, 1.98 mmol)
and NaOH (0.198 g, 4.95 mmol) in THF:water (20 mL, 1:1) was added
di-tert-butyl dicarbonate (1.30 g, 5.94 mmol) in THF (4 mL). The reaction
mixture was stirred at room temperature for 4 hours followed by the
addition of 3.0 equiv. of di-tert-butyl dicarbonate and 2.5 equiv. of
NaOH. The mixture was stirred at room temperature for another 3 days. The
mixture was concentrated and extracted with CHCl3 (3×20 mL).
The combined organic phases were dried with K2CO3, filtered and
concentrated. The crude residue was purified by column chromatography on
silica using CHCl3 as eluent gave 0.200 g (26%) of the pure product
as a solid brown solid: MS (posESI) m/z 386 (M+H).

[0110]1-tert-Butyl
4-(4-{methyl[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarb-
oxylate (intermediate 14 after reduction according to Method A) (75 mg,
0.15 mmol) was dissolved in methanol (5 mL) and treated with 1N HCl in
ether (20 mL). After stirring overnight, the product precipitated and was
collected by filtration, washed with ether and dried. Yield 60 mg (92%)
of an off white solid.

[0186]4-Fluoro-naphtalene-1-sulfonylchloride was dissolved in DCM. The
amine (1.2 eq) was added followed by pyridine (3 eq). The mixture was
stirred for 2 h at ambient temperature, diluted with DCM and washed 2
times with HCl (1M). The organic layer was filtered through a silica plug
to afford the sulfonylamide.

##STR00349##

[0187]The sulfonamide and the amine (5 eq) were dissolved in DMSO and
stirred at 100° C. overnight. The DMSO solution was added dropwise
to water to give a precipitate. After centrifugation, the solvent was
decanted and the procedure was repeated. The residue was dissolved in
MeOH and converted to HCl salt by adding HCl in ether (2 M) and
evaporation.

##STR00350##

[0188]To a solution of the sulfonamide in acetone, K2CO3 (3 eq)
was added followed by MeI (1.2 eq). The mixture was stirred overnight,
filtered through a short silica plug and evaporated to give the
methylated sulfonamide.

[0230]4-Fluoronaphthalene-1-sulfonyl chloride--To a stirred solution of
1-fluoronaphthalene (8.0 g, 55 mmol) in concentrated trifluoroacetic acid
(40 ml), chlorosulfonic acid was added slowly (15 min) at 0° C.
The mixture was stirred at room temperature for an additional 2 hours and
then added slowly onto a stirred ice slurry. The formed precipitate
filtered off, washed with cold water and dried in vacuo to give the title
compound (7.3 g) as a white solid.

[0255]The final product was prepared according to Method F: Use of
4-fluoro-N-(3-trifluoromethylhiophenyl)naphthalene-1-sulfonamide afforded
the title compound (0.08 g), gave 0.060 g of the desired product, yield
85%, purity 96%.

[0280]3-Cyanomethylpyridine-N-oxide--Hydrogenperoxide (17 ml, 30% ww) was
added to a mixture of 3-cyanomethylpyridine (11 g, 93 mmol) and glacial
acetic acid (55 ml) and heated at 100° C. overnight. The mixture
was diluted with water (70 ml) and MnO2 (5.0 g) was carefully added
and stirred for 5 hours (check peroxide content with peroxide sticks),
and only small amounts of peroxide was left. The mixture was concentrated
in vacuo to 40 ml and diluted with methanol (40 ml), filtered through a
short plug of silica, and washed with methanol (400 ml). The filtrate
were concentrated and recrystallized from chloroform and hexane to give
the title compound (9.5 g, 76%). 1H NMR (CDCl3) δ 8.16
(s, 2H), 7.32 (s, 2H), 3.73 (s, 2H); MS m/z (M+1) 135.

[0299]tert-Butyl
4-(5-amino-1-benzofuran-7-yl)-piperazine-1-carboxylate-1-Methyl-4-(5-Nitr-
o-1-benzofuran-7-yl)-piperazine (1 eq) and tert-butyl
4-(5-nitro-1-benzofuran-7-yl)-piperazine-1-carboxylate (1 eq) were
reduced to aromatic amine with Raney-Ni and hydrazine (10 eq) in
THF/Ethanol (1:4), 3 h at room temperature. The reaction mixture are
filtered through celite pad, the volatiles are evaporated and the crude
is used in the next reactions.

[0317]The ability of a compound according to the invention to bind a
5-HT6 receptor, and to be pharmaceutically useful, can be determined
using in vivo and in vitro assays known in the art.

(a) 5-HT6 Intrinsic Activity Assay

[0318]Antagonists to the 5-HT6 receptor were characterized by
measuring inhibition of 5-HT induced increase in cAMP in HEK 293 cells
expressing the human 5-HT6 receptor (see Boess et al. (1997)
Neuropharmacology 36: 713-720). Briefly, HEK293/5-HT6 cells were
seeded in polylysine coated 96-well plates at a density of 25,000/well
and grown in DMEM (Dulbecco's Modified Eagle Medium) (without phenol-red)
containing 5% dialyzed Foetal Bovine Serum for 48 h at 37° C. in a
5% CO2 incubator. The medium was then aspirated and replaced by 0.1
ml assay medium (Hanks Balance Salt Solution containing 20 mM HEPES, 1.5
mM isobutylmethylxanthine and 1 mg/ml bovine serum albumin). After
addition of test substances, 50 μl dissolved in assay medium, the
cells were incubated for 10 min at 37° C. in a to 5% CO2
incubator. The medium was again aspirated and the cAMP content was
determined using a radioactive cAMP kit (Amersham Pharmacia Biotech,
BIOTRAK RPA559). The potency of antagonists was quantified by determining
the concentration that caused 50% inhibition of 5-HT (at [5-HT]=8 times
EC50) evoked increase in cAMP, using the formula
Ki=IC50/(1+[5HT]/EC50).

[0319]The compounds in accordance with the invention have a selective
affinity to 5-HT6 receptors with Ki values between 0.5 nM and 5
μM. The compounds show good selectivity for 5-HT1a, 5-HT2a,
5-HT2a, 5-HT2b, 5-HT2c.

[0321]Obese (ob/ob) mouse is selected as the primary animal model for
screening as this mutant mouse consumes high amounts of food resulting in
a high signal to noise ratio. To further substantiate and compare
efficacy data, the effect of the compounds on food consumption is also
studied in wild type (C57BL/6J) mice. The amount of food consumed during
15 hours of infusion of compounds is recorded.

[0322]Male mice (obese C57BL/6JBom-Lee and lean wild-type C57B1/6JBom;
Bomholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g
(obese) and 25 g (lean) are used in all the studies. The animals are
housed singly in cages at 23±1° C., 40-60% humidity and have
free access to water and standard laboratory chow. The 12/12-h light/dark
cycle is set to lights off at 5 p.m. The animals are conditioned for at
least one week before start of study.

[0323]The test compounds are dissolved in solvents suitable for each
specific compound such as cyclodextrin, cyclodextrin/methane sulfonic
acid, polyethylene glycol/methane sulfonic acid, saline. Fresh solutions
are made for each study. Doses of 30, 50 and 100 mg kg-1 day-1
are used. The purity of the test compounds is of analytical grade.

[0324]The animals are weighed at the start of the study and randomized
based on body weight. Alzet osmotic minipumps (Model 2001 D; infusion
rate 8 μl/h) are used and loaded essentially as recommended by the
Alzet technical information manual (Alza Scientific Products, 1997;
Teeuwes and Yam, 1976). Continuous subcutaneous infusion with 24 hours
duration is used. The minipumps are either filled with different
concentrations of test compounds dissolved in vehicle or with only
vehicle solution and maintained in vehicle pre-warmed to 37° C.
(approx. 1 h). The minipumps are implanted subcutaneously in the
neck/back region under short acting anesthesia (metofane/enflurane). This
surgical procedure lasts approximately 5 min. It takes about 3 h to reach
steady state delivery of the compound.

[0325]The weight of the food pellets are measured at 5 p.m. and at 8 p.m.
for two days before (baseline) and one day after the implantation of the
osmotic minipumps. The weigh-in is performed with a computer assisted
Mettler Toledo PR 5002 balance. Occasional spillage is corrected for. At
the end of the study the animals are killed by neck dislocation and trunk
blood sampled for later analysis of plasma drug concentrations.

[0326]The plasma sample proteins are precipitated with methanol,
centrifuged and the supernatant is transferred to HPLC vials and injected
into the liquid chromatography/mass spectrometric system. The mass
spectrometer is set for electrospray positive ion mode and Multiple
Reaction Monitoring (MRM with the transition m/z 316 221). A linear
regression analysis of the standards forced through the origin is used to
calculate the concentrations of the unknown samples.

[0327]Food consumption for 15 hours is measured for the three consecutive
days and the percentage of basal level values is derived for each animal
from the day before and after treatment. The values are expressed as
mean±SD and ±SEM from eight animals per dose group. Statistical
evaluation is performed by Kruskal-Wallis one-way ANOVA using the percent
basal values. If statistical significance is reached at the level of
p<0.05, Mann-Whitney U-test for statistical comparison between control
and treatment groups is performed.

[0328]The compounds according to the invention show an effect in the range
of 50-200 mg/kg.